Background: Heart failure with preserved ejection fraction (HFpEF) is induced by multiple risk factors including obesity, hypertension, diabetes, and aging, but how these individual comorbidities act synergistically to cause HFpEF is unclear. We hypothesize that obesity and hypertension cause transcriptional and epigenetic remodeling that drive heart failure progression. Methods: Adult male mice were administered high fat diet (HFD, 60% kcal from fat), L-NAME (0.5g/L) or both in combination (2-hit mouse model of HFpEF) for 15 weeks. After phenotypic characterization, we conducted RNA sequencing on isolated cardiomyocytes to identify the transcriptomic signatures of individual risk factors. We also extensively characterized extracellular matrix (ECM) remodeling through novel decellularization approaches. Results: Both L-NAME alone and HFD+L-NAME (HFpEF) mice had elevated systolic blood pressure (153.1 mmHg in HFpEF, 140.3 mmHg in L-NAME and 113.3 mmHg in control, p=0.0001) and both HFD alone and HFpEF had impaired exercise capacity (49 min in HFpEF, 35.1 min in HFD and 139 min in control, p=0.0001). Diastolic dysfunction was only observed in the HFpEF group (E/e’ -39.8 v. -24.7 in control, p=0.0001, LVEDP 18.9 mmHg v. 3.1 mmHg in control, p=0.0001). Transcriptome analyses of HFpEF, L-NAME, HFD, and control revealed that L-NAME clustered closest to the HFpEF group, suggesting hypertension is a major contributor to HFpEF pathology at 15 weeks. Downregulated gene programs were generally shared between treatment groups, including glycolysis (Eno1, Ldhb, Gapdh) and cytoskeleton organization (Actr2, RAN, Cfl2). Gene programs such as voltage gated channels (Kcnq2, Cacna1e, Cacnag4) and chemokine signaling (Cxcr2, Xcr1, Ccr2) were only upregulated in HFpEF and L-NAME groups. Activated genes shared between HFD and HFpEF related to metabolic stress (Nr4a3, Pik3r1, Pla2g4e). In addition to picrosirius histology revealing mild fibrosis, we examined key components of the ECM to characterize previously unknown remodeling of the muscle-matrix interface. We identified that the basement membrane (indicated by laminin) is significantly expanded in the HFpEF condition, concomitant with upregulation of collagens and genes coordinating ECM organization (Col26a1, Col22a1, Ltbp1). These findings reveal the development of HFpEF through the contributions of distinct risk factors and identify new features of ECM remodeling in the disease.
Gromova et al. (2025) studied this question.